The use of blood substitutes in the medical field is widely practiced and, more particularly, in instances in which blood is not available when it is preferable to use a substance other than blood, use of animal blood as a blood substitute is considered hazardous primarily because of incompatibility. Typical instances wherein human blood transfusion is required include, surgery, injury with bleeding, gastrointestinal hemorrhage and diffuse hemorrhagic disorders of various types. Also of interest are situations such as military battles wherein blood transfusions are required in the battlefield.
A widely performed surgery requiring blood is cardiac surgery, and cardiac surgery requiring cardiopulmonary bypass requires large amounts of blood for the cardiopulmonary bypass hardware, or if blood is not used in the cardiopulmonary bypass system, some other type of volume replacement is essential.
During cardiopulmonary bypass for cardiac surgery, the patient's total blood volume of approximately 5 or 6 liters in an adult is removed from the right atrium and passed through a bubble oxygenator by gravity flow or through a membrane oxygenator by a pump and then returned to the patient usually via the thoracic aorta; the functions of both the patient's heart as well as the patient's lungs are assumed by the cardiopulmonary bypass system. With the cardiopulmonary bypass system functioning, the patient no longer requires the functioning of his own heart and lungs, the chest cavity can now be entered, the lungs can be deflated if necessary for proper exposure of the operative field, and the heart can be opened and repaired.
However, there are known complications with surgery requiring cardiopulmonary bypass which are quite familiar to the medical profession, and understood, to a degree. For example, it is almost unheard of for a patient or an animal to survive after more than 6, or at the most, 12 hours of cardiopulmonary bypass. Fortunately most patients require much shorter periods of time on bypass, most now probably no greater than 1 hour, many less, some even as short a time as 20 minutes or even 15 minutes "on pump". Excellent tabulation of the complications of the procedure have been tabulated in man, always of course influenced by the surgery itself, so that it is not possible to differentiate clearly the effect of cardiopulmonary bypass itself upon morbidity and mortality, from the effect of the particular surgical procedure upon these two factors. But in animal studies, the morbidity and mortality of cardiopulmonary bypass alone, can be more clearly identified.
There is room for improvement in cardiopulmonary bypass procedure which had its application in man in the early 1950's. A sensitive indicator of a potential problem is current data from multi-institutional studies of a degree of memory deficit, perhaps permanent, and seemingly relatively common, especially in patients over age 60 or thereabouts, who undergo surgery utilizing cardiopulmonary bypass.
As the 6 or so liters of the patient's blood is allowed to enter the cardiopulmonary bypass system of biocompatible tubing, oxygenator, pump, heat exchanger and arterial filter, it is essential that this system be completely devoid of air, and that it contain a "priming fluid" to replace all air in the system, all air in the items noted above, and some of the air in the "venous reservoir" of the system. The volume of this priming fluid in the average adult case will be about 2.0 liters, perhaps a little more.
In the past, blood has been used as a priming fluid but for various reasons is no longer used at least not totally; and a degree of "hemodilution" is preferred at most surgical centers. Hemodilution reduces viscosity of the blood, currently considered an advantage in relation to blood flow. Currently it is common practice to prime the system with sterile water to which has been added those elements of blood consisting of molecules, other than protein, red blood cells, white blood cells and platelets.
A solution containing the above components is referred to as a physiologic crystalloid priming solution. If some, but not all, of the normal blood crystalloids are omitted, the solution is referred to simply as a crystalloid prime.
The crystalloid prime does not contain albumin, globulin, or other blood proteins, and therefore its colloid osmotic pressure is missing, although it is normo-osmolar in respect to crystalloids. There is, however, a problem in this regard, and there is a second problem as related to the oxygen carrying capacity of this priming fluid.
The osmolarity of normal human plasma is about 303 mOsmoles per liter of water, and standard crystalloid priming solutions for cardiopulmonary bypass often approximate this value. However, these solutions contain no protein, hence these primes possess no colloid osmotic pressure, differing in this way from normal human blood which contains about 7.0 grams per cent protein, mainly albumin and globulin, and the effect upon fluid transfer from the intravascular space to the intracellular space is very great. Fluid accumulation in the patient has been estimated at 1.0 or more liters per square meter of body surface area per hour of bypass, with additional fluid retention persisting into the post-operative patients not receiving blood replacement.
Water retention and fluid accumulation in the body (a condition known in the medical field as anasarca) can be reduced by the administration of colloidal substitutes such as dextran, hydroxyethyl-starch and others.
The fact is, however, that cardiopulmonary bypass is known to be associated with tendency to interstitial water retention, and perhaps intracellular water retention, the net effect of which may be related to morbidity associated with this procedure.
The normal hematocrit of most patients (the packed red cell volume) is about 40 to 45%. With hemodilution induced by crystalloid prime, most surgical centers employ hemotocrit levels of 20 to 25% while on pump, which means that the oxygen carrying capacity of each milliliter of blood traversing the patient's circulatory tree is now capable of carrying about 50% as much oxygen as before hemodilution. It may be that this reduction in oxygen carrying capacity of the blood and perhaps aggravated by anasarca and its aggravation of impaired oxygen transfer to the cell is the component, or one of the components in the reduced memory currently being reported in a significant percentage of cardiopulmonary bypass procedure patients. This diminished oxygen carrying capacity can be ameliorated by the addition of an oxyreplete substance such as perfluorochemicals.
Basically, an artificial replacement fluid should have the following properties to be feasible:
It should function for at least several hours as well as normal blood having a hematocrit of about 45%.
It should not be toxic.
It should be sterile and pyrogen free.
It should be free of any antigens, i.e., it should not activate the body's immune system; nor should it require any blood typing analysis.
It should have a reasonable "shelf-life" at least as long as, or longer than, fresh whole blood.
While many different approaches have been disclosed for providing a viable oxygen transport system, for instance, U.S. Pat. Nos. 3,937,821; 3,962,439; 4,173,654; 4,186,253; 4,397,870 and 4,423,077, none of these patents discloses a hyperosmolar blood substitute for preventing anasarca and enhancing oxygenation in a patient undergoing cardiopulmonary bypass surgery.
Because of the problems associated with cardiopulmonary bypass surgery such as anasarca and reduced memory as described above, after considerable research and experimentation applicant has discovered new blood substitutes which substantially reduce or eliminate the above problems associated with said surgery.
The prior art is silent regarding a hyperosmolar blood substitute which has increased oxygen carrying capacity.